Chronic tobacco use is associated with a significant increase in heart disease and many forms of cancer; even the health of non-tobacco users is negatively affected by second-hand smoke. The potential benefits to the individual and society that would come from a better understanding of the factors that contribute to nicotine dependence are enormous. Conditioning is one important factor that contributes to the addiction cycle. Research and theory on drug conditioning most often treats nicotine as an unconditioned stimulus or reinforcer that enters into an association with other stimuli (cigarette, situational cues) that reliably co-occur with its physiological effects. An understudied area that is also important for the development and tenacity of nicotine dependence is the ability of the pharmacological effects of nicotine to serve as an interoceptive stimulus for other reinforcing events (peer acceptance, alcohol, work breaks, stress relief, etc.). Indeed, there has been a recent rise in investigators' and practitioners' awareness of the role of interoceptive conditionin to a wide range of psychopathologies and diseases-including addiction. We have developed a preclinical model to study interoceptive conditioning with nicotine. Rats that have an appetitive learning history with nicotine will show evidence of conditioning controlled by the nicotine stimulus; that is, anticipatory food-seeking. The most provocative finding to date is that conditioning to the nicotine stimulus can be weakened by repeated non- reinforced presentation of an alternative drug (i.e., extinction) that shares interoceptive stimulus effects with nicotine. This transfer of extinction has been seen with varenicline (the smoking cessation aid Chantix(R)), bupropion (the smoking cessation aid Zyban(R)), and nornicotine (a potential smoking cessation aid that is a metabolite of nicotine and minor alkaloid in tobacco). The proposed research will build programmatically on this exciting finding by more closely examining novel approaches to deepening transfer of extinction, hence diminishing the control of nicotine over acquired appetitive behavior. In doing so, the experiments in this application introduce new methods for studying interoceptive stimuli to the field, begin to fill a significant gap in the scientific literature, advance our understanding of extinction processes involving nicotine, and elucidate the nature of the nicotine stimulus and treatment-relevant ligands. PUBLIC HEALTH RELEVANCE: Tobacco use reflects a major health problem that results from an addiction to nicotine. With an estimated annual economic cost around $167 billion, this nicotine addiction is associated with a significant increase in heart disease and many forms of cancer; the health of non-tobacco users is also negatively affected by second-hand smoke. The potential benefits that would come from a better understanding of chronic tobacco use are enormous and this benefit is the primary reason the long-term goal of our research program is to elucidate interoceptive conditioning processes contributing to nicotine dependence.